This invention relates to the use of loratadine to treat arrhythmias including atrial fibrillation in mammals.
Estimates for the prevalence of atrial fibrillation (AF) in the US range from 2.2-3 million patients. It is commonly a disease of the elderly (affecting 13% of 70-80 year olds) and is therefore expected to increase as a result of changing demographics. AF is responsible for 1/3 of all strokes in people over 65 years, and has associated costs of approximately $9 billion/year. Current therapy is to allow patients to remain in AF and reduce the ventricular rate by pharmacological means. This is considered safe, although it is believed that there are significant benefits of being in sinus rhythm (vs. rate control).
There are some new therapies for the treatment of arrhythmias under examination. For example, dofetilide is a selective inhibitor of the rapid component of the delayed rectifier potassium current which prolongs the action potential duration and the effective refractory period in a concentration dependent manner. Clinical studies have demonstrated that dofetilide is effective in treating patients with atrial arrhythmias.
There is also ongoing research related to the Kv 1.5 channel blockers. Regulation of the resting membrane potential and action potential duration of the heart is mediated by four principal K+ currents: an inwardly rectifying current (I.sub.K1), a transient outward current (I.sub.To) and rapid (I.sub.Kr) and slow (I.sub.Ks) delayed rectifying currents. At the molecular level, recent studies have shown I.sub.K1 may be produced by at least 3 genes from the Kir family, while the remaining currents are mediated by members of the voltage-dependent potassium channel (Kv) superfamily.
The Kv1.5 channel produces a current identical to the ultrarapid outwardly rectifying K+ current (I.sub.Kur) identified in the atria. Inhibitors of the Kv1.5 channel have been shown to prolong action potential in the human atrial myocytes Fedida D. Et al. Circ Res 1993;73:210-216.
Delpon, Eva, et al., in Cardiovascular Research 35 (1997) 341-350 discloses that loratadine blocked hKv1.5 channels in a concentration-, voltage-, time- and use-dependent manner but only at concentrations much higher than therapeutic plasma levels in man. This would indicate the possibility of antiarrhythmic properties for this compound. However, the use of loratadine for such indication is only a possibility since, for example, there have been at least 2 reported cases of atrial fibrillation in the literature with loratadine use both with and without a history of similar arrhythmia (Good A P Am J. Cardiol 1994;Jul. 15;74(2):208-9 and Luck J et al J allergy Clin Immunol 1995;95:282). This opens up the possibility that loratadine, although having properties which may prevent atrial arrhythmia, may also have the potential for initiating this arrhythmia.
Although there are some therapies for the treatment of atrial fibrillation there is a continuing search in this field of art for new therapies.